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A puzzling multisystem disorder in three children, had genetic experts scrambling to identify what went wrong. Their research provides important information on key biological events occurring in human development and offers clues for treatment.

"This syndrome illuminates a very important pathway in early human development — a sort of master switch that controls many other genes," said study leader Ian D. Krantz, M.D., co-director of the Individualized Medical Genetics Center at The Children's Hospital of Philadelphia (also acronymed CHOP). Krantz, a medical geneticist, is an attending physician in the hospital's comprehensive human genetics program.

Krantz is the senior author of the study, published in Nature Genetics. His co-study leader is Katsuhiko Shirahige, Ph.D., of the Institute for Molecular and Cellular Biosciences at the University of Tokyo, also the home institution of first author Kosuke Izumi.

The central finding of their report is that mutations in the gene AFF4 disrupt a crucial group of proteins called the super elongation complex (SEC).

SEC controls the transcribing of DNA into RNA, enabling genes to be expressed in a developing embryo. Timing is tightly regulated, so any timing interference can disturb normal development in a variety of ways.

Krantz: "Because the SEC involves such a crucial process in cell biology, it has long been a focus of study, particularly in cancer. CHOPS syndrome is the first example of a human developmental disorder caused by germline mutations in the SEC."

Germline mutations originate in the developing embryo. They are passed along to multiple organs and biological systems as harmful effects. A mutated AFF4 gene produces mutated proteins, which accumulate causing a cascade of abnormalities in other genes controlled by AFF4. Krantz: "Mutations of the AFF4 gene int the SEC can damage the heart and skeleton, and lead to intellectual disability, among other effects."

Researchers sequenced the exomes (protein-coding portions of DNA) of three unrelated children bein treated at CHOP for a puzzling complex of developmental disorders. All three patients had symptoms similar to those found in patients with Cornelia deLange syndrome (CdLS), a rare multisystem disease long studied at the CHOP hospital. Krantz himself led research that discovered the first causative gene for CdLS in 2004.

DNA analysis of gene expression patterns determined that the new syndrome is genetically distinct from CdLS, even while sharing some common molecular mechanisms. Although only the three children in the study are known to definitely have CHOPS syndrome, Krantz expects the CHOPS diagnoses to increase with the dissemination of this latest discovery and the growing spread of fast, lower-cost gene-sequencing technology.

The research findings offer practical and emotional benefits for families, said Krantz. Physicians may now order more appropriate tests to monitor and manage specific medical issues arising from CHOPS syndrome. "This also means families and children can end their 'diagnostic odyssey'--the frustrating procession of tests and unsuccessful treatments that often occurs in trying to find an answer for families who have a child affected by a complex, undiagnosed disorder," he added.

Researchers have shown that CHOPS syndrome is a de novo condition — caused by a new mutation arising in a single egg or sperm, but not present in the patient's parents — that affects the child.

Doctors can now reassure parents that this illness is extremely unlikely to recur in any subsequent children.

Like many other rare genetic diseases, CHOPS syndrome does not yet have an effective treatment; physicians like Krantz can only manage the symptoms. But the research team's insight into the basic biology of this disorder may lay the groundwork for future treatment of this disease, and possibly other SEC diseases if they exist.

Abstract
Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome. Direct molecular interaction of the SEC, cohesin and RNAP2 was demonstrated. These data support a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin.

Note: After the embargo ends, see this blog posting about the "medical odyssey" experienced by families of children with this syndrome: http://www.research.chop.edu/blog/finding-new-genetic-syndrome-ends-medical-odyssey-families/

The National Institutes of Health (grant HD052860) supported this study, as did the Cornelia deLange Syndrome Foundation and MEXT, a Japanese government agency.

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.